MMP24 as a Target of YAP Is a Potential Prognostic Factor in Cancer Patients
MMP24 as a Target of YAP Is a Potential Prognostic Factor in Cancer Patients
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DOI：
10.3390/bioengineering7010018
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发表时间：
2020-03-01
影响因子：
4.6
通讯作者：
Kawauchi, Keiko
中科院分区：
文献类型：
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作者：
Sugimoto, Wataru;Itoh, Katsuhiko;Kawauchi, Keiko
癌细胞周围的细胞外基质(ECM)在肿瘤进展过程中变得更加坚硬，它通过调节基因表达和肌动蛋白细胞骨架的重塑来影响癌细胞的侵袭和增殖等行为。在本研究中，我们发现编码基质金属蛋白酶(MMP24)-24的MMP24是YAP的一个新的靶基因，YAP是一种被称为机械转导的转录辅助激活因子。我们首先检测了基质硬度对MCF-7人乳腺癌细胞MMP24表达的影响，发现在硬基质上生长的细胞MMP24的表达明显高于在软基质上生长的细胞。YAP基因的敲除可显著降低MMP24的表达。相反，结构性活性YAP的表达增加了MMP24启动子的活性。染色质免疫沉淀(ChIP)实验证实YAP与MMP24启动子结合。这些结果表明，ECM硬化促进了YAP的激活，从而诱导MMP24的表达。根据人类蛋白质图谱数据库，MMP24表达较低的乳腺癌患者总体存活率较低。因此，在肿瘤进展过程中，在僵硬的ECM环境下，MMP24可能负向调节癌细胞的侵袭性。
The extracellular matrix (ECM) surrounding cancer cells becomes stiffer during tumor progression, which influences cancer cell behaviors such as invasion and proliferation through modulation of gene expression as well as remodeling of the actin cytoskeleton. In this study, we show that MMP24 encoding matrix metalloproteinase (MMP)-24 is a novel target gene of Yes-associated protein (YAP), a transcription coactivator known as a mechanotransducer. We first examined the effect of substrate stiffness on MMP24 expression in MCF-7 human breast cancer cells and showed that the expression of MMP24 was significantly higher in cells grown on stiff substrates than that on soft substrates. The MMP24 expression was significantly reduced by knockdown of YAP. In contrast, the expression of constitutively active YAP increased MMP24 promoter activity. In addition, binding of YAP to the MMP24 promoter was confirmed by the chromatin immunoprecipitation (ChIP) assay. These results show that ECM stiffening promotes YAP activation, thereby inducing MMP24 expression. Based on the Human Protein Atlas database, breast cancer patients with lower MMP24 expression exhibit the worse survival rates overall. Thus, MMP24 may negatively regulate the aggressiveness of cancer cells under the stiff ECM environment during tumor progression.